KR101688996B1 - Composition comprising Tramadol and Celecoxib in the treatment of pain - Google Patents

Abstract

The present invention relates to pharmaceutical compositions comprising tramadol and celecoxib and to their use as medicaments or analgesics, more particularly as medicaments or analgesics for the treatment of severe or moderate pain of inflammatory elements.

Description

The present invention relates to a composition containing tramadol and celecoxib in the treatment of pain,

The present invention relates to pharmaceutical formulations comprising Tramadol and Celecoxib and to their use as medicaments or analgesics, in particular for the treatment of severe or moderate pain.

Pain is a complex response categorized into functional, sensory, autonomic, motor, and affective factors. The adaptive element is considered to be the activation of internal pain control and movement to plan the escape response, while the sensory aspect includes information about the stimulus location and intensity. Emotional factors appear to include not only the negative emotions induced by the context and memory of pain stimuli, but also the evaluation of pain unpleasantness and threats of stimuli.

In general, pain states are classified as chronic and acute. Chronic pain includes pain due to unknown origin, such as neuropathic pain and chronic inflammatory pain, such as arthritis, fibromyalgia. Acute pain generally occurs following non-neural tissue injury, such as surgery or inflammation, or tissue damage due to migraine. Pain may also be divided into severely painful to moderate pain to strictly different levels of light pain.

There are many drugs known to be useful for pain management or treatment.

Opioids are often used as analgesics for pain. Morphine derivatives have been recognized as therapeutic agents to alleviate acute pain in humans. Analgesic effects are obtained through their action on morphine receptors, preferably on the [mu] receptor. As these morphine derivatives, mention may be made of morphine, codeine, petidine, dextrorphoxyphenemethadone, linepofane.

One of the morphine derivatives, which when administered orally, has very good results and is widely commercialized is tramadol and is also available as a physiologically acceptable salt, especially chlorohydrate. Tramadol is an analgesic that has a central effect by activating opioid receptors and enhancing the neuronal monoamin synaptic concentration of neurons. Tramadol whose compound name is 2- (dimethylaminomethyl) -1- (3-methoxyphenyl) cyclohexanol is of the formula:

Tramadol

This structure exhibits two different chiral centers and therefore the molecule may exist as another diastereoisomer, among which the tramadol is the cis-partial isomer. The enantiomers (1 R , 2 R ), or (1 S , 2 S ) are also known as (+) - tramadol and (-) - tramadol, all of which are racemic tramadol Contributes to activity in different ways.

"( Rac )" according to the present invention is defined as an abbreviation of a racemate and therefore " rac -tramadol" or " rac tramadol" refers to the racemic tramadol (cis-partial isomer ).

Thus, "( rac ) -tramadol.HCl" or "( rac ) tramadol.HCl" is defined as hydrochloride of racemic tramol (cis-partial isomer) as mentioned above.

It is known from the prior art that the compounds are not sufficiently opioid-like and non-opioid-like. Several studies have demonstrated that tramadol is an opioid agonist, while clinical experience has shown that it does not exhibit typical side effects of many types of opioid agonists, such as respiratory depression, constipation, or tolerance .

Because of their shortcomings, opioids used as analgesics in the treatment of pain were not always available in high doses or repeatedly. The action of the opioid is described, for example, in J. Jaffe in " Goodman and Gilman ' s, The Pharmacological Basis of Therapeutics ", 8 ^th edition; Gilman et al .; Pergamon Press, New York, 1990, Chapter 22, pages 522-573.

As a result, in order to reduce the amount of opioid required to provide an equivalent degree of analgesia, a combination of opioids with other drugs other than opioids analgesics has been provided. Of these combinations, the association of non-steroidal anti-inflammatory agents (NSAIDs) with tramadol has been reported to be of particular interest (EP-0 546 676).

US 5,516,803 discloses the combination of tramadol and non-steroidal anti-inflammatory drugs (NSAIDs), particularly ibuprofen, and includes combinations such as tramadol HCl and non-steroidal anti- inflammatory agents such as ibuprofen , And the ratio of the composition from 1: 1 to 1: 200 synergistically reduces the improvement of analgesic action and undesirable accompanying symptoms.

The US 6,558,701 patent discloses that tramadol and diclofenac and "to treat moderate to severe pain, " the International Health Organization (WHO) recommends that opioid analgesics and non- - < / RTI > a combination of steroidal analgesics. "

One interesting NSAIDs in combination with tramadol is sold as Celecoxib drug, the name of which is 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -pyrazol- (4-methylphenyl) -3- (trifluoromethyl) -pyrazol-1-yl] -benzenesulfonamide. Celecoxib is an anti-inflammatory, pain-relieving drug and is one of the most used remedies for chronic muscular-skeletal inflammatory disease. Its empirical formula is _{C 17 H 14 F 3 N 3} O 2 S.

Celecoxib

Celecoxib is an oral, selective cyclooxygenase-2 (COX-2) inhibitor and is an inhibitor of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis (Goldenberg MM, Celecoxib, a selective cyclooxygenase-2 inhibitor for the treatment of rheumatoid arthritis and osteoarthritis, Clin . Ther . 1999, 21, 1497-513). This high selectivity minimizes gastrointestinal adverse drug reactions (e. G., Gastric ulcers) that are common to non-selective NSAIDs, while allowing celecoxib and other COX-2 inhibitors to reduce inflammation do.

Cyclooxygenase is responsible for the production of prostaglandins. Two isoforms, COX-1 and COX-2 were identified. COX-2 has been shown to be induced by pro-inflammatory stimulation and is an isoform of the enzyme that is supposed to play a major role in the synthesis of pain, inflammation, and heat prostanoid regulators. COX-2 has also been implicated in ovulation, implantation and closure of the ductus arteriosus, regulation of renal function, and central nervous system function (heat induction, pain recognition and cognitive function). It can also play a role in the recovery of ulcers. Although COX-2 has been identified in tissues around human gastric ulcers, its association with ulcer recovery has not been established.

WO00 / 51685 discloses, on the one hand, a tramadol substance selected from:

(+) - and (-) - tramadol, racemic tramadol, N-oxide tramadol and O-desmethyl-tramadol (both as free bases or salts, or as solvates or polymorphs) A separate stereoisomer comprising a semi-compound or a mixture thereof);

On the other hand, a pharmaceutical composition comprising a selective COX-2 inhibitor in combination with a celecoxib as described in a COX-2 inhibitor drug. The focus of this application is on demonstrating the combination of tramadol and JT-522.

This application now discloses tramadol, especially ( rac ) -tramadol hydrochloride, which has opioid activity, and celecoxib (especially in its neutral form), especially for severe or moderate pain, especially for pain with inflammatory elements Or a pharmaceutically acceptable salt thereof.

It is therefore an object of the present invention to a pharmaceutical composition comprising ( rac ) tramadol HCl and celecoxib or a pharmaceutically acceptable salt or hydrate combination thereof.

In general, the separate active components of the pharmaceutical compositions according to the invention, tramadol and celecoxib, have their own disadvantages when used alone.

Therefore, tramadol chloride, used orally, is very bitter, sometimes making the drug difficult to swallow and reducing the patient's ability to hold. In addition, as noted above, defects associated with opioids - their side effects - limit their use and should therefore be given at lower doses and should be used less often as an analgesic for the pain relief generally needed do. Celecoxib, on the other hand, is known to be slightly soluble in water, which further limits its use as a pharmaceutical formulation.

It is an object of the present invention to provide a pharmaceutical composition comprising an NSAID such as an opioid such as tramadol and a celecoxib having a level of efficacy similar to that obtainable when each active substance is used alone, same.

With better safety results at higher doses and / or

By showing synergistic effects - by using less of each component, still exhibits the desired activity, thus making it possible to reduce the side effects associated with each element; And / or

▶ Provide a new and more effective method for the treatment of severe or moderate pain, especially those with inflammatory factors.

Other desirable improvements / benefits of the novel pharmaceutical composition include the use of a pharmaceutical composition that is currently insufficient for current treatment, such as sciatica or frozen shoulder or central sensitization (central pain syndrome) Or symptom or related pain and activity in its subtype.

Most preferably, the new pharmaceutical composition should combine most, if any, of one or more, most preferably all of these advantages.

The pharmaceutical compositions according to the present invention show improved properties compared to other active ingredients alone.

In one preferred embodiment of the pharmaceutical composition according to the invention, the celecoxib is in a neutral form.

Celecoxib is weakly acidic with a pKa of 11.1 and therefore its "neutral form" according to the invention is defined as free (non-salt form) forms of celecoxib, And carries the load.

In one further embodiment of the pharmaceutical composition according to the invention, the ratio of ( rac ) -tramadol.HCl to celecoxib ranges from about 1: 1 to about 1: 300 or from about 1: 1 to about 300: 1 weight ratio.

In one further embodiment of the pharmaceutical composition according to the invention the ratio of ( rac ) -tramadol.HCl to celecoxib ranges from about 1: 1 to about 1: 300 or from about 1: 1 to about 300: 1 molar ratio.

In one embodiment of the pharmaceutical composition according to the invention, the molecular ratio of ( rac ) -tramadol.HCl to celecoxib ranges from about 1: 1 to about 1:30 or from about 1: 1 to about 30: 1 .

In one embodiment of the pharmaceutical composition according to the present invention, the ratio of ( rac ) -tramadol.HCl to celecoxib has a mole ratio of about 1: 1 to about 1:30 or about 1: 1 to about 30: 1.

In one embodiment of the pharmaceutical composition according to the present invention, the mole ratio of ( rac ) -tramadol.HCl to celecoxib is from about 1: 1 to about 1: 5 or from about 1: 1 to about 5: 1.

Another advantage is that the association of two active agents in a unique specie appears to have better pharmacokinetic / harmacodynamic (PKPD), including better blood-brain barrier transit capability , Which helps to treat pain.

Two parts of the pharmaceutical composition are well known drugs used for a long time in the world. Due to its importance in the treatment of painful symptoms of tramadol and the well-known properties of celecoxib in the field of medical instruction, it is a further object of the present invention to provide a pharmaceutical composition comprising ( rac ) -tramadol.HCl and celecoxib .

Therefore, the invention also relates to a medicament containing a pharmaceutical composition comprising ( rac ) -tramadol HCl and celecoxib according to the invention as described above, further comprising a pharmaceutically acceptable excipient excipient).

The pharmaceutical or pharmaceutical composition according to the present invention may be in any form suitable for human and / or animal, preferably human, including infants, children and adults, and may be manufactured by standard processes known to those skilled in the art . Second Edition, Aulton, ME (Ed. Churchill Livingstone, Edinburgh (2002); "Encyclopedia of Pharmaceutical Technology", Second Edition, Swarbrick, New York (2002); "Modern Pharmaceutics" Fourth Edition, Banker GS and Rhodes CT (Eds.) Marcel Dekker, Inc. New York 2002 "The Theory & Practice of Industrial Pharmacy "Lachman L., Lieberman H. And Kanig J. (Eds.), Lea & Febiger, Philadelphia (1986), each of which is incorporated herein by reference The composition of the medicament may be varied depending on the method of administration.

The pharmaceutical or pharmaceutical formulations according to the invention can be administered parentally in combination with a typical injectable liquid carrier such as, for example, water or a suitable alcohol. Typical pharmaceutical excipients, such as stabilizers, solubilizing agents, and buffering agents, may be included in such injectable compositions. Such pharmaceutical or pharmaceutical formulations may be injected intramuscularly, intraperitoneally, or intravenously, for example.

The pharmaceutical or pharmaceutical formulations according to the invention may also be formulated in solid or liquid form, with orally administrable compositions containing one or more physiologically acceptable carriers or excipients. Such compositions may contain typical ingredients such as binding components, fillers, lubricants, and acceptable hygroscopic agents. The compositions may be in the form of tablets, pellets, granules, capsules, lozenges, aqueous or oily solutions, suspensions, emulsions, or dry powders suitable for reconstitution with water or other suitable liquid medium for intermediate or controlled release prior to use Any convenient form can be used, such as in the form of a < / RTI > Multiparticulates such as pellets or granules can be filled, for example, with capsules, compressed with tablets, or suspended in suitable liquids.

Modified Release Drug Delivery Technology "Rathbone, MJ Hadgraft, J. and Roberts, MS (Eds.), Marcel Dekker, Inc., New York (2002); "Handbook of Pharmaceutical Controlled Release Technology" Wise, DL (Ed.), Marcel Dekker, Inc. New York, (2000); Oral Drug Delivery "Encyclopedia of Controlled ", Takada, K. and Yoshikawa, H., " Controlled Drug Delivery" Vol, I, Basic, Bruck, SD (Ed.), CRD Press Inc., Boca Raton Drug Delivery, Mathiowitz, E. (Ed.), John Wiley & Sons, Inc., New York (1999), Vol. 2, 728-742; (Ed.), John Wiley & Sons, Inc., New York (1999), Vol. 2, 698-728. Each of which is incorporated herein by reference and partially disclosed.

The pharmaceutical or pharmaceutical formulations according to the invention may also comprise forms of enteric coatings, the decomposition of which depends on the pH-value. The coating of the medicament can be passed undecomposed from above and each pharmaceutical composition and their components are separated in the intestinal tract. Preferably the enteric coating is dissolved at a pH of from 5 to 7.5. Suitable materials and methods of making are known in the prior art.

Typically, the medicament or pharmaceutical formulation according to the invention comprises 1-60% by weight of a combination of ( rac ) -tramadol.HCl and celecoxib and one or more auxiliary substances (additives / excipients) as defined herein, 40-99% by weight.

The compositions according to the invention may also be administered topically or suppository.

The daily dose for humans and animals varies greatly depending on the species or species of each species or other factors such as age, sex, weight or degree of disease, and the like. Preferably, the daily dose for humans is in the range of 10 to 2000 milligrams of active substance administered once or several times daily.

An additional embodiment according to the present invention is a method of treating pain, preferably pain, acute pain, chronic pain, neuropathic pain including diabetic neuropathy, hyperalgesia, allodynia and cancer Cancer pain and osteoarthritis; As well as severe or moderate pain; (Rac) -tramadol.HCl and < RTI ID = 0.0 > tramadol, < / RTI > and < RTI ID = 0.0 & 0.0 > celecoxib < / RTI > The use of the pharmaceutical composition can be in particular for the treatment of severe or moderate pain of inflammatory factors such as, for example, rheumatoid arthritis, ankylosing spondylitis, sciatica and scabies.

Additional aspects in accordance with the present invention are methods for treating pain, acute pain, chronic pain (acute and chronic pain), neurogenic pain including diabetic neuropathy or diabetic peripheral neuropathy, nociceptive pain, (Such as visceral pain and / or somatic pain), mild pain and severe pain to moderate pain, hyperalgesia, pain associated with central sensitization, hyperlipidemia or cancer pain and osteoarthritis, fibromyalgia fibromyalgia); ( Rac ) -tramadol.HCl and celecoxib according to the invention for the treatment of rheumatoid arthritis, ankylosing spondylitis, frozen shoulder or sciatica, or for use as analgesics, and to pharmaceutical compositions according to the present invention . Additional aspects in accordance with the present invention are methods for treating pain, preferably acute pain, or neurogenic pain including, preferably, acute pain, chronic pain (acute and chronic pain), diabetic neuropathy or diabetic peripheral neuropathy, Visceral pain and / or body pain), mild pain and severe pain to moderate pain, pain associated with central sensitization, allodynia or cancer pain and osteoarthritis, fibromyalgia; ( Rac ) -tramadol HCl and celecoxib according to the invention for the treatment of rheumatoid arthritis, ankylosing spondylitis, frozen shoulder and sciatic nerve pain in accordance with the present invention. Therefore, the present invention also relates to a method for treating pain, preferably acute pain, chronic pain (acute and chronic pain), diabetic neuropathy or neuropathic pain including diabetic peripheral neuropathy, invasive pain (visceral pain and / Or body pain), mild pain and severe pain to moderate pain, hyperalgesia, pain associated with central sensitization, allodynia or cancer pain and osteoarthritis, fibromyalgia; Rheumatoid arthritis, ankylosing spondylitis, frozen shoulder or sciatica, in the manufacture of a medicament for the treatment of rheumatoid arthritis, ankylosing spondylitis, frozen shoulder or sciatica.

A further aspect of the present invention relates to a method of treating pain, preferably acute pain, chronic pain, neurogenic pain including diabetic neuropathy, hyperalgesia, allodynia and cancer pain, fibromyalgia and osteoarthritis, as described above; As well as severe or moderate pain; And the use of the pharmaceutical composition according to the invention in the manufacture of a medicament for the treatment of rheumatoid arthritis, ankylosing spondylitis, sciatica and scabies. Preferably, the use is provided in the form of a medicament or a pharmaceutical formulation according to the invention as described above. This agent is particularly applied to treat severe to moderate pain with inflammatory factors such as, for example, rheumatoid arthritis, ankylosing spondylitis, sciatica and scabies. A further aspect of the invention relates to a method for treating pain, preferably acute pain, chronic pain (acute and chronic pain), diabetic neuropathy or neuropathic pain including diabetic peripheral neuropathy, Pain (visceral pain and / or body pain), mild pain and severe pain to moderate pain, hyperalgesia, pain associated with central sensitization, allodynia or cancer pain and osteoarthritis, fibromyalgia; For the manufacture of a medicament for the treatment of rheumatoid arthritis, ankylosing spondylitis, frozen shoulder or sciatic nerve pain.

Another object of the present invention is to provide a patient in need thereof with a sufficient amount of a pharmaceutical composition comprising ( rac ) -tramadol HCl and celecoxib according to the present invention as described above to treat pain, preferably acute pain , Chronic pain, neurogenic pain including diabetic neuropathy, hyperalgesia, allodynia and cancer pain, fibromyalgia and osteoarthritis; As well as severe or moderate pain; It is also a method of treatment of rheumatoid arthritis, ankylosing spondylitis, sciatica, and frogs. This method of treatment is particularly concerned with the treatment of severe or moderate pain with inflammatory factors such as, for example, rheumatoid arthritis, ankylosing spondylitis, sciatica and scabies. Another related object is to provide a patient in need thereof with a sufficient amount of a pharmaceutical composition comprising ( rac ) -tramadol HCl and celecoxib according to the present invention as described above to treat pain, preferably acute pain, chronic Neurological pain including pain (acute and chronic pain), diabetic neuropathy or diabetic peripheral neuropathy, invasive pain (visceral pain and / or body pain), mild pain and severe pain to moderate pain, hyperalgesia , Pain associated with central sensitization, allodynia or cancer pain and osteoarthritis, fibromyalgia; Rheumatoid arthritis, ankylosing spondylitis, frozen shoulder or sciatica.

"Pain" is defined by the International Association for the Study of Pain (IASP), which is associated with such actual or potential tissue injury, or which is sensory and emotional (IASP, Classification of chronic pain, 2 ^nd edition, IASP Press (2002), 210). Although pain is always subjective, it can be categorized as its cause or syndrome. One classification for naming subtypes of pain is to divide the common pain syndrome into subtypes of acute and chronic pain or - depending on the intensity of the pain - into mild, moderate, and severe pain . Another definition of generalized pain syndrome is also the "nociceptive" (caused by the activity of the nociceptor), "neuropathic" (caused by the damage or disorder of the nervous system) And central pain (central pain syndrome).

"Sciatica" or "sciatic neuritis" is defined herein as a set of symptoms that includes pain resulting from irritation of the sciatic nerve or its source.

"Frozen shoulder" or "adhesive capsulitis" refers herein to a connective tissue or shoulder capsule itself surrounding the shoulder joint that causes chronic pain, inflammation, It is defined as symptoms.

"Ankylosing spondylitis" or "Morbus Bechterew" is a chronic, inflammatory arthritis and autoimmune disease. It mainly affects sacroilium in the bone and joints and pelvis, and ultimately leads to fusion of the bones.

"Central sensitization related pain" / "central pain syndrome" refers to neurological disorders caused by damage or impairment of the central nervous system (CNS) including the brain, State. Such syndromes can be caused by seizures, multiple sclerosis, tumors, epilepsy, trauma of the brain or spinal cord, or Parkinson's disease.

"Nociceptive pain" is defined as the type of pain generated by activation of the nociceptor. It can be divided into somatic pain and visceral pain. "Internal pain" is generally derived from organs, while "(deep) body pain" is derived from ligaments, tendons, bones, blood vessels, fasciae, and muscles.

Figure 1:
A: Other combinations (1: 1, 1: 3, and 3: 1) at different ratios of tramadol, celecoxib, and celecoxib and racimetramine hydrochloride in a foot wound model of rat post- Dose response curve of the anti-hyperalgesic effect of the anti-hyperglycemic agent.
B : Isobologram showing a significant (p < 0.01) synergy relationship in thermal hyperalgesia. All data are presented as ± SEM (n = 10-13 per dose group).

The invention will now be described with the aid of the following examples. This description is given by way of example only and is not intended to be limiting of the invention.

Example

Example  One

Tramadol  Hydrochloride and Celecoxib  Preparation of dose composition

The combination of racemic tramadol hydrochloride and celecoxib was prepared with different ratios of ( rac ) -tramadol.HCl: celecoxib (1: 1, 1: 3, and 3: 1). All drugs and combinations were dissolved in 0.5% hydroxypropyl methylcellulose in distilled water and administered via intraperitoneal (ip) route with a volume of 10 ml / kg per rat. Table 1 shows the various ratios produced at various concentrations.

Rat After surgery  In the pain model, Hyper-Algerian  effect

The aim of this study was to compare the combination of tramadol / celecoxib, especially racemic tramadol hydrochloride, and other molar ratios of celecoxib (1: 1, 1: 3 and 3: 1) in rat models of post- To determine the efficacy and potency as an analgesic of the compositions containing them. Thermal hypersensitivity (hyperalgesia) was performed using plantar test assays (Hargreaves et al., Pain 1988, 32, 77) to ensure the reliability of the efficacy and efficacy of the tested compounds.

Experimental Design:

animal

Male, Wistar rats (120-160 g, Haran, Italy) stayed in the mildly controlled room for at least 5 days before testing. Food and water were given ad libitum in random amounts until testing.

Animal dose

The rats were dissolved in a suspension of 0.5% hydroxypropylmethylcellulose in distilled water and a composition containing a combination of racim ramadol hydrochloride and celecoxib in different ratios was all administered into the peritoneum. The dose was 10 ml / kg. The anti-hyperalgesia response of the animal was then measured 60 minutes after administration of the composition.

Operation

The rats were anesthetized with 3% isofluorane and passed through the skin and fascia on the soles of the feet of the feet, starting from 0.5 cm proximal to the base of the heels and wound 1 cm vertically to the claws. Finally, the surface of the foot was stitched with a sutured stitch on a sutured breaded silk (3.0).

Rat  Evaluation of analgesic effects in post-surgical pain

The drug was administered 4 hours after surgery (foot injury); After 60 minutes of product administration, it was tested.

Rat  Thermal hypersensitivity in postoperative pain Hyper Algecia )

Thermal hypersensitivity or hyperalgesia was assessed by measuring the response to thermal stimulation (Ugo Basile plantar test) using a Hargreves instrument that selectively increased the temperature of the individual feet (Dirig, et al., J Neurosci Methods, 1997, 76 , 183) Animals were placed in a metacrylic of this apparatus with a crystal bottom. The adaptation time in us was about 10 minutes. Thermal stimulation from a lamp applied under the crystal floor and applied to the feet was applied at least one minute between both stimuli to avoid learning behaviors. It is possible for the rat to avoid foot freely when feeling the heat-induced discomfort (pain) from the lamp; Then the switch is turned off and the latency time to avoid the response is recorded in seconds. To avoid damage to the animal's feet, the lamp was automatically switched off after 32 seconds. Hyperalgesia is defined as an increase in the response to painful pain, and the effect of analgesics on the test compound seems (partially) as if latency is restored to normal. (Dirig, et al., J. Pharmacol Expt Therap. 1998, 285, 1031).

Analysis of synergy

The synergistic relationship between tramadol and celecoxib was determined through isobologram analysis as described by RJ Tallarida, et al., Life Sci., 1989, 45, 947. This procedure is based on the total amount of the mixture (i.e., ED ₅₀ or Zt) required to exhibit an apparent synergistic anti-hyperalgesia effect at the 50% dose level and the total amount (ED ₅₀ add or Zadd ). &Lt; / RTI &gt; If a specific fixed-ratio of Zt &lt; Zadd is determined, then the composition has a synergistic anti-hyperalgesia effect. Both the ED ₅₀ t and ED ₅₀ add values are arbitrarily varied. The ED ₅₀ t is determined through a dose-response curve for the specific fixed-ratio of the components; The ED ₅₀ add is calculated from the ED ₅₀ value of each drug. Then Zt is compared with Zadd through Student's t-test.

result:

In this study, a dose response curve of a composition comprising a combination of racemic tramadol hydrochloride and celecoxib in different ratios (1: 1, 1: 3 and 3: 1) was obtained (see Figure 1A). Thermal hypersensitivity When measured, all drugs were inducing sufficient efficacy.

All ratios of the combination of racimetramine hydrochloride and celecoxib exhibited a synergistic effect of blocking thermal hyperalgesia in post-operative pain rats. The 1: 1 and 3: 1 ratios significantly improved the anti-hyperalgesia effect by a factor of four. The 1: 3 ratio improved the anti-hyperalgesia effect by a factor of 1 (see Table 2 and Figure 1B).

conclusion

A composition comprising a combination of racimetramine hydrochloride and celecoxib shows a synergistic relationship to block thermal hyperalgesia in a post-op pain model of rat soles.

Claims (7)

( rac ) -tramadol HCl and celecoxib or a pharmaceutically acceptable salt or hydrate thereof, wherein the ratio ( rac ) -tramadol.HCl to the celecoxib ratio molecular ratio) is a molar ratio of 1: 1 to 1: 5 or 1: 1 to 5: 1, or for use as an analgesic. The pharmaceutical composition of claim 1, wherein the celecoxib is in a neutral form. 2. The pharmaceutical composition according to claim 1, wherein the ratio of ( rac ) -tramadol.HCl to celecoxib is in a molar ratio of 1: 1. 4. The method of any one of claims 1 to 3, wherein the pain includes acute pain, chronic pain, diabetic neuropathy or diabetic peripheral neuropathy. Neuropathic pain, nociceptive pain, mild pain and severe pain or moderate pain, hyperalgesia, central sensitization, Related pain, allodynia or cancer pain and osteoarthritis, fibromyalgia; Rheumatoid arthritis, ankylosing spondylitis, frozen shoulder or sciatica. &Lt; RTI ID = 0.0 &gt; 11. &lt; / RTI &gt; delete delete delete

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